Over the past 30 years, the incidence of hepatocellular carcinoma (HCC) in the United States has tripled. Chronic hepatitis C virus (HCV) infection has been the major underlying reason for this increase. However, only a small fraction of chronic HCV carriers develop HCC. Variation in the risk of HCC among chronic HCV carriers may be caused by complex interplay between genetic and environmental factors. Several studies indicate a positive association between history of liver cancer in first-degree relatives and risk of HCC development, supporting the potential impact of genetic factors in HCC development. The mechanisms of HCV-induced HCC and genetic susceptibility factors for HCC in chronic HCV carriers are not well studied. Candidate gene-based association studies have implicated a few genetic variants in HCC etiology, but none have been validated as meaningful genetic factors for HCV-associated HCC in the U.S. or for clinical outcomes of HCC. We hypothesize that unique host genetic factors can predict HCC risk in non-viral cases, whereas other markers may predict HCC development in patients with chronic HCV infection and clinical outcome in HCC, including response to therapy. The recent explosion of genome-wide association studies (GWASs) has identified numerous genetic susceptibility loci for many cancers. To date, however, no HCC GWAS has been published in the U.S., in part because of difficulty in recruiting large numbers of HCC patients, a result of HCC's natural history and clinical features: 1) HCC is uncommon, especially in the U.S.; 2) HCC is typically diagnosed at a late stage with poor survival; and 3) end- stage chronic liver disease is a major underlying burden in HCC patients. Another barrier to genetic studies of HCC is the lack of comprehensive data on epidemiological and environmental risk factors to control for confounding effects. Only through multi-institutional collaboration can a GWAS of an uncommon cancer such as HCC be performed in the U.S. We propose a GWAS of HCC using 19 North American institutions, which will enable the integration of genetic, environmental, and clinical data. A total of 1715 HCC cases and 3254 controls will be included in the discovery phase, and results will be validated in 2410 cases and 4420 controls. All cases will be frequency-matched to control subjects by age, race and sex. The impact of the validated genotypes on the incidence of HCC development will be assessed in 1100 patients with cirrhosis and who are under surveillance for the development of HCC and enrolled in an NCI-funded follow-up study. In addition to risk assessment, the effect of genetic variation on overall survival of HCC patients will be determined in all cases including an exploratory analysis of progression free survival in HCC patients who have been treated with sorafenib, the current standard of care for advanced HCC. Finally, we plan to explore our objective in Hispanics, Blacks, and Asians for future minority-specific genetic studies in U.S. OurGWAS will provide a detailed understanding of the genetic risk factors for HCC development and prognosis in the U.S.